缺氧虽然可以杀死正常细胞,但却是各种肿瘤细胞的特征之一,并且有助于肿瘤发生耐药和转移,而碳酸酐酶IX仅过表达于缺氧肿瘤细胞膜,可以催化二氧化碳与水反应生成碳酸氢根,提高肿瘤微环境的酸性,有利于肿瘤生长繁殖。不过,传统的碳酸酐酶抑制剂缺乏靶向性,无法针对缺氧肿瘤细胞膜表面的碳酸酐酶IX。
2019年9月6日,美国科学促进会《科学》旗下《科学进展》发表中国科学院国家纳米科学中心、中国科学院大学的研究报告,利用短肽纳米纤维与小分子碳酸酐酶抑制剂自动结合,成功实现了针对人类三阴性乳腺癌细胞MDA-MB-231表面碳酸酐酶IX的缺氧靶向疗法,大大增强了碳酸酐酶抑制剂抗肿瘤的有效性和选择性。
碳酸酐酶IX还可引起肿瘤细胞内吞作用,促进纳米纤维在缺氧条件下被肿瘤细胞有选择地摄入,而且纳米纤维结构的体积可以随着肿瘤微环境酸性升高而增大,随后导致肿瘤细胞内酸性囊泡被撑破,并且可以阻断保护性自噬。纳米纤维结构随着肿瘤细胞微环境而变化的多功能作用令人印象深刻,可以有选择地杀死肿瘤细胞,为缺氧肿瘤提供了治疗新策略。此外,体内研究表明,该短肽纳米纤维与小分子碳酸酐酶抑制剂自动结合以后,对于乳腺肿瘤具有强大的抗转移和抗血管生成作用,尤其可以显著增强化疗药物多柔比星的抗肿瘤效果。
因此,该研究结果表明,该纳米技术凭借其生物相容成分和独特低氧疗法,可以大大提高现有的化疗效果,并为缺氧癌症靶向治疗提供了新的方向。
Sci Adv. 2019 Sep 6;5(8):eaax0937.
New power of self-assembling carbonic anhydrase inhibitor: Short peptide-constructed nanofibers inspire hypoxic cancer therapy.
Jiayang Li, Kejian Shi, Zeinab Farhadi Sabet, Wenjiao Fu, Huige Zhou, Shaoxin Xu, Tao Liu, Min You, Mingjing Cao, Mengzhen Xu, Xuejing Cui, Bin Hu, Ying Liu, Chunying Chen.
National Center for Nanoscience and Technology of China, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX-targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX-related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.
DOI: 10.1126/sciadv.aax0937
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